IL10 is a predominantly anti-inflammatory cytokine that is critical in setting immune response amplitude. Genetic variation in IL10 or IL10R expression or function is associated with susceptibility to autoimmune and inflammatory diseases. The efficacy of many immunomodulatory therapies is IL10 dependent. Nevertheless, pharmacotherapy with IL10 has shown little benefit in several diseases, and in some experimental settings overexpression or pharmacologic treatment with IL10 can even promote autoimmune inflammation. We hypothesized that differences in the lineage specific effects of IL10 may in part explain the variability of its activity in vivo. To dissect IL10's lineage specifi actions, we generated mice conditionally deficient in the IL10-selective chain of the IL10 receptor, IL10R?. In preliminary studies, we analyzed deficiency of IL10R? on T cells, Foxp3+ regulatory T cells, B cells and macrophage in a model autoimmune disease, experimental allergic encephalomyelitis (EAE). Our findings indicated that pro- and anti- inflammatory functions of IL10 segregate in a lineage dependent manner. Further, IL10 has heterogeneous actions within a lineage, and these may have opposing effects on that lineage's pathogenicity. In this proposal we will use EAE as a model system to explore how the lineage specific effects of IL10 influence the development and progression of autoimmunity. We demonstrated that, surprisingly, the T cell response to IL10 worsened EAE. We hypothesize that IL10 helps sustain the effector T cells (Teff) responsible for immunopathology by inhibiting their terminal differentiation and promoting their survival. In Aim 1, we will determine how IL10's actions on T cells promote immunopathology in EAE. We will address mechanisms of IL10-mediated modulation of T cell proliferation, survival, and memory in vivo, how the immune environment influences the production and effects of IL10, how IL10R signal quality, kinetics, and magnitude influence its T-specific activities, and relevant cellular sources for IL10 affecting the T cell response. In contrast to Teff, the IL10 response of Foxp3+ regulatory T cells suppressed EAE. We hypothesize that IL10 acts to support Treg longevity and suppressive capacity during inflammation. In Aim 2 we will analyze IL10's influence on Treg survival, proliferation, maturation, and function during EAE. IL10 acts globally to limit EAE severity, yet its T cell-specific actions promote disease. In Aim 3 we will identify and begin to characterize the cell lineages responsible for IL10's palliative effects in EAE. Dissecting how IL10 variably influences different cell lineages during autoimmunity will provide us with an improved mechanistic understanding of IL10's regulatory actions, and insights that will aid in the rational design of ne therapeutics that modulate inflammation through the IL10 pathway.